Metabolic and pharmacological observations during drug treatment of epilepsy

摘要

The thesis reports studies on patients with epilepsy. The effects of two newly introduced anticonvulsant agents are discussed with regard to the seizure control, side effects, serum levels and their effect on the metabolism of other anticonvulsant drugs when used in combination. Some of the metabolic changes induced by anticonvulsant medication are reported. The introduction to the thesis gives an account of the general mode of action of anticonvulsant drugs, and indicates the continual search for the ideal anticonvulsant. The methods used in various analyses in this thesis are described. The thesis is then divided into two sections. The first deals with the comparative trial of the two newly introduced anticonvulsant agents, i.e. sodium valproate (EPILIM) and clonazepam (RIVOTRIL). The two drugs were studied in a cross-over trial in 32 chronic epileptic patients who were showing poor control; one of the trial drugs was added to the existing therapy for a period of 12 weeks, after which the patients took the second drug. Sodium valproate was the more effective drug with the least side effects. However, sodium valproate had more effect on other serum anticonvulsant drug levels: it increased the serum levels of pheno-barbitone and reduced those of phenytoin in some patients. The second section of the thesis deals with two of the changes in metabolism induced by the chronic intake of anticonvulsant drugs. Chapters 3, 4 and 5 deal with the incidence of serum IgA depletion, the effect of anticonvulsants on secretory IgA, the relation of serum IgA depletion to the HLA status, and the effect anticonvulsants have on lymphocyte protein synthesis. The results show that roughly one fourth of the patients studied had reduced serum IgA levels, and this directly related to the intake of phenytoin. The reduction in serum IgA was not found to be reflected on the active form of IgA, viz, secretory IgA; although found to be reduced, this was to a much lesser degree than that of the serum. The reduction in serum IgA in patients on phenytoin was related to the higher incidence of a specific HLA pattern in these patients. HLA-A2 was much more prevalent in these patients than in patients on the same medication but who did not have a low serum IgA level. Lymphocyte protein synthesis was found to be reduced in all patients on anticonvulsants when compared to controls. During the IgA studies serum folate was measured, and it was found to be reduced in 90% of the patients. This was further studied in Chapters 7 and 8. Serum folate was found to be reduced in most of the patients studied. Those who had the lowest serum folate levels had CSF examination for folate, which was found to be reduced as well. The effects of treating patients with low serum and CSF folate is reported. The treatment was with folic acid or with 5-formyltetrahydrofolate. The effects of treatment on seizure frequency, serum anticonvulsant levels and CSF amine metabolites (HVA and HIAA) were studied. The results show that CSF folate increased more with 5-formyltetrahydrofolate treatment. Serum phenytoin levels were reduced with treatment, and the levels of HVA and HIAA were reduced with 5-formyl-tetrahydrofolate; there was, however, no effect on seizure frequency.